Discovery and validation of autosomal dominant Alzheimer's disease mutations.

TitleDiscovery and validation of autosomal dominant Alzheimer's disease mutations.
Publication TypeJournal Article
Year of Publication2018
AuteursHsu, S, Gordon, BA, Hornbeck, R, Norton, JB, Levitch, D, Louden, A, Ziegemeier, E, Laforce, Jr, R, Chhatwal, J, Day, GS, McDade, E, Morris, JC, Fagan, AM, Benzinger, TLS, Goate, AM, Cruchaga, C, Bateman, RJ, Karch, CM
Corporate AuthorsDominantly Inherited Alzheimer Network (DIAN)
JournalAlzheimers Res Ther
Date Published2018 Jul 18

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease that is clinically characterized by progressive cognitive decline. Mutations in amyloid-β precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) are the pathogenic cause of autosomal dominant AD (ADAD). However, polymorphisms also exist within these genes.METHODS: In order to distinguish polymorphisms from pathogenic mutations, the DIAN Expanded Registry has implemented an algorithm for determining ADAD pathogenicity using available information from multiple domains, including genetic, bioinformatic, clinical, imaging, and biofluid measures and in vitro analyses.RESULTS: We propose that PSEN1 M84V, PSEN1 A396T, PSEN2 R284G, and APP T719N are likely pathogenic mutations, whereas PSEN1 c.379_382delXXXXinsG and PSEN2 L238F have uncertain pathogenicity.CONCLUSIONS: In defining a subset of these variants as pathogenic, individuals from these families can now be enrolled in observational and clinical trials. This study outlines a critical approach for translating genetic data into meaningful clinical outcomes.

Alternate JournalAlzheimers Res Ther
PubMed ID30021643
PubMed Central IDPMC6052673
Grant ListK01 AG046374 / AG / NIA NIH HHS / United States
UF1 AG032438 / AG / NIA NIH HHS / United States
AG046374 / / National Institute on Aging /
UF1AG032438 / / National Institute on Aging /